Diarrheal diseases afflict U.S. Veterans both at home and abroad. While the causes may be more acute overseas and more chronic in U.S., diarrhea in these conditions is a result of altered electrolyte (e.g. Na, Cl) and fluid transport in the intestine. For example, alterations in epithelial electrolyte transporters (e.g. Na:H and Cl:HCO3 exchange) is caused by immune inflammatory mediators known to be elevated in the mucosa of the chronically inflamed intestine (e.g. Inflammatory bowel disease, IBD). Thus, while the concept of immune regulation of electrolyte transport in IBD is fairly well accepted, specifically which of the many immune inflammatory pathways may regulate which transport pathway to cause diarrhea is poorly understood. Given this background, using a technique to isolate relatively pure and viable villus and crypt cells from the rabbit intestine, we demonstrated that coupled NaCl absorption occurs via the dual operation of Na:H and Cl:HCO3 exchange in the BBM of villus cells. We also demonstrated that in the chronically inflamed intestine coupled NaCl absorption is inhibited secondary to the inhibition of Cl:HCO3, but not Na:H exchange on the BBM of villus cells. The mechanism of inhibition of Cl:HCO3 is secondary to diminished affinity of the transporter for Cl and thus, it is likely a post-translational mechanism of regulation. We identified this Cl:HCO3 exchanger in the rabbit ileal villus cell BBM to be SLC26a3 (DRA). Then we demonstrated that the inhibition can be alleviated by a broad spectrum immune modulator (corticosteroids). Additional preliminary studies indicated a specific and unique immune mechanism of regulation of DRA in the chronically inflamed intestine. Finally, preliminary data from the human IBD small intestine demonstrated similar changes in coupled NaCl absorption. These novel observations have given rise to the overall hypothesis of this proposal which is that inhibition of Cl:HCO3 exchange in villus cells is uniquely regulated by immune-inflammatory mediators produced in the chronically inflamed intestine. Therefore, the overall aim is to determine the mechanisms of immune regulation of Cl:HCO3 exchange in villus cells in the chronically inflamed intestine. Better understanding of the immune regulation of NaCl absorption by the villus cells may provide the foundation to develop more novel, efficacious and specific immune therapies for the most common morbidity of IBD, namely diarrhea.